Dipeptidyl Peptidase 4 (DPP4) Review Uncovers Multidimensional Roles in Glucose, Fibrosis, Inflammation, and Cancer.

Type 2 diabetes mellitus (T2DM) is a major global health burden characterized by impaired glucose homeostasis. Dipeptidyl peptidase 4 (DPP4) is a key enzyme that degrades incretin hormones like GLP-1, thereby regulating blood glucose. While conventional small-molecule DPP4 inhibitors are established T2DM treatments, DPP4's ubiquitous expression and diverse functions suggest broader pathological involvement beyond glucose metabolism, including fibrosis, inflammation, and cancer, warranting exploration of novel targeted interventions.

This systematic review synthesized current research on dipeptidyl peptidase 4 (DPP4), delineating its established enzymatic functions and mechanisms in glucose metabolism. The authors comprehensively discussed its novel pathological roles in fibrotic, inflammatory, and oncological processes. Furthermore, the review evaluated recent progress in diverse DPP4 intervention strategies, including conventional small-molecule inhibitors, emerging DPP4-inhibitory peptides, and advancements in DPP4-specific antibodies, drawing insights from both in vitro and in vivo studies across various disease models.

The review systematically confirmed dipeptidyl peptidase 4 (DPP4)'s critical enzymatic function in cleaving N-terminal X-Pro or X-Ala dipeptides, primarily degrading incretin hormones and thus elevating blood glucose. Beyond its well-known role in glucose metabolism, the synthesis of evidence highlighted DPP4's emerging significance as a potential biomarker and intervention target in fibrosis, inflammation, and cancer.

Notably, DPP4-inhibitory peptides demonstrated significant efficacy in vitro for controlling high blood glucose, suggesting a promising alternative to small-molecule inhibitors. Advancements in DPP4-specific antibodies were also identified as creating new opportunities for both diagnosing and treating a range of DPP4-related diseases. The review deepened the understanding of DPP4's multifaceted biological functions and its complex associations with various pathologies, providing a robust theoretical basis for optimizing existing and developing novel DPP4-targeted therapeutic strategies.